This application is presented with the long term objective of understanding important underlying mechanisms for the pathogenesis of Krabbe disease. Krabbe disease is a devastating genetic pediatric sphingolipidosis whose progression is characterized by the accumulation of the lipid psychosine. Unfortunately, only limited progress has been made using enzyme replacement methods for the treatment of this disease. It is thought that one of the reasons that treatment has been met with only limited success is that too much damage has been done to the nervous system before enzyme replacement is able to exert an effect. With this in mind, the importance of studying early disease mechanisms becomes quite clear. For example, demyelination, which is commonly thought to be the major insult that results from Krabbe disease, may be only one of many mechanisms by which the disease alters the central nervous system. As has been described recently, neurons appear to be susceptible to disease processes independently of whether or not they have had significant contact with myelin or myelinating cells. This suggests that pharmacological interventions to protect neuronal cell populations early on may be of some benefit in treating these patients. The specific aims of this study are designed to address this possibility. In order to achieve these goals, this application proposes to use primary neuronal culture from a Krabbe disease mouse model to investigate whether signaling mechanisms important to neuron survival are compromised during disease progression. Specifically, our recently accepted manuscript has highlighted that psychosine can interfere with signaling by altering signaling platforms known as lipid rafts within the cell membrane. This mechanism for disease progression will be looked at in neurons to see whether it may drive the loss of neuorprotective signals that would be important for the maintenance of these cells during disease. In addition, this proposal suggests the use of alternative pharmacological methods for the induction of neuroprotective signaling which will help to describe whether these drugs in combination with enzyme replacement may provide a more effective treatment and thus a better outcome for children suffering from Krabbe disease. FOR THE PUBLIC: Krabbe disease is a devastating and lethal disorder of the nervous system that affects many children throughout the world. This project is designed to provide a basis for significant alterations in the current approach for the treatment of this disease and is aimed at improving the length and quality of life of these patients.